Journal article
Contribution of intraflagellar transport to compartmentalization and maintenance of the photoreceptor cell
Proceedings of the National Academy of Sciences - PNAS, Vol.121(34), e2408551121
08/20/2024
DOI: 10.1073/pnas.2408551121
PMCID: PMC11348033
PMID: 39145934
Abstract
The first steps of vision take place in the ciliary outer segment compartment of photoreceptor cells. The protein composition of outer segments is uniquely suited to perform this function. The most abundant among these proteins is the visual pigment, rhodopsin, whose outer segment trafficking involves intraflagellar transport (IFT). Here, we report three major findings from the analysis of mice in which ciliary transport was acutely impaired by conditional knockouts of IFT-B subunits. First, we demonstrate the existence of a sorting mechanism whereby mislocalized rhodopsin is recruited to and concentrated in extracellular vesicles prior to their release, presumably to protect the cell from adverse effects of protein mislocalization. Second, reducing rhodopsin expression significantly delays photoreceptor degeneration caused by IFT disruption, suggesting that controlling rhodopsin levels may be an effective therapy for some cases of retinal degenerative disease. Last, the loss of IFT-B subunits does not recapitulate a phenotype observed in mutants of the BBSome (another ciliary transport protein complex relying on IFT) in which non-ciliary proteins accumulate in the outer segment. Whereas it is widely thought that the role of the BBSome is to primarily participate in ciliary transport, our data suggest that the BBSome has another major function independent of IFT and possibly related to maintaining the diffusion barrier of the ciliary transition zone.The first steps of vision take place in the ciliary outer segment compartment of photoreceptor cells. The protein composition of outer segments is uniquely suited to perform this function. The most abundant among these proteins is the visual pigment, rhodopsin, whose outer segment trafficking involves intraflagellar transport (IFT). Here, we report three major findings from the analysis of mice in which ciliary transport was acutely impaired by conditional knockouts of IFT-B subunits. First, we demonstrate the existence of a sorting mechanism whereby mislocalized rhodopsin is recruited to and concentrated in extracellular vesicles prior to their release, presumably to protect the cell from adverse effects of protein mislocalization. Second, reducing rhodopsin expression significantly delays photoreceptor degeneration caused by IFT disruption, suggesting that controlling rhodopsin levels may be an effective therapy for some cases of retinal degenerative disease. Last, the loss of IFT-B subunits does not recapitulate a phenotype observed in mutants of the BBSome (another ciliary transport protein complex relying on IFT) in which non-ciliary proteins accumulate in the outer segment. Whereas it is widely thought that the role of the BBSome is to primarily participate in ciliary transport, our data suggest that the BBSome has another major function independent of IFT and possibly related to maintaining the diffusion barrier of the ciliary transition zone.
Details
- Title: Subtitle
- Contribution of intraflagellar transport to compartmentalization and maintenance of the photoreceptor cell
- Creators
- Tylor R Lewis - Duke University HospitalCarson M Castillo - Duke University HospitalNatalia V Klementieva - Duke University HospitalYing Hsu - University of IowaYing Hao - Duke UniversityWilliam J Spencer - Duke University HospitalArlene V Drack - University of IowaGregory J Pazour - University of Massachusetts Chan Medical SchoolVadim Y Arshavsky - Duke University Hospital
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.121(34), e2408551121
- Publisher
- NATL ACAD SCIENCES
- DOI
- 10.1073/pnas.2408551121
- PMID
- 39145934
- PMCID
- PMC11348033
- ISSN
- 1091-6490
- eISSN
- 1091-6490
- Grant note
- Blindness Inc. (Duke University)Fighting Blindness Canada
This work was supported by the NIH grants EY030451 (V.Y.A.), EY005722 (Duke University), EY033763 (T.R.L.), EY022372 (G.J.P.), and EY025580 (University of Iowa), an Unrestricted Award from Research to Prevent Blindness Inc. (Duke University), Fighting Blindness Canada (A.V.D.), InVision2020 (A.V.D.), and the Keech Professorship (A.V.D.) . We thank Joan Kalnitsky (Duke University) for technical assistance.
- Language
- English
- Date published
- 08/20/2024
- Academic Unit
- Stead Family Department of Pediatrics; Ophthalmology and Visual Sciences
- Record Identifier
- 9984697058802771
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